Our ability to characterize somatic DNA alterations promises to revolutionize medicine, allowing us to predict disease onset/progression and craft individualized pharmacologic therapies with an unprecedented level of precision. This transformative potential of genomics has elevated the importance of identifying and isolating the most diagnostically useful tissue from the body. Today, most tissues are extracted via surgery or standard biopsy. Unfortunately, these methods are invasive, expensive, time-consuming, and imprecise. Because macroscopic inspection cannot identify microscopic tissue features and excision is crude, both sensitivity and specificity are lacking. Current excisional approaches either fail to sample critical microscopic disease or extract a composite of normal and diseased tissues, complicating downstream genomic analysis. In this proposal, we will address this key barrier in the field by developing a new technology termed in vivo laser capture microdissection (IVLCM). IVLCM uses a minimally invasive device to at once conduct comprehensive microscopy in the living patient, identify tissue with microscopic evidence of disease, and laser capture the targeted tissues onto the device. After the device is removed from the body, the tissues are processed for subsequent genetic, molecular and histopathologic analysis. By making tissue procurement more accurate and accessible, IVLCM will allow genomic diagnostics to be used routinely in clinical practice, expanding the reach of precision medicine. The clinical focus of this grant is Barrett's esophagus (BE), a precancerous condition with unmet clinical needs in screening and surveillance that can be addressed by an improved tool for precise isolation and genotyping of aberrant tissues. Our proposed solution for BE is a tethered IVLCM pill that can be swallowed by unsedated subjects, making it much easier and less expensive to administer than standard endoscopic biopsy. Following development of the technology, we will validate the capabilities of capsule IVLCM for BE surveillance and screening in clinical studies that compare genomic analysis of IVLCM-extracted tissues to that of conventional biopsies and cells acquired using a blind-sampling screening device.